The Genetic Epidemiology Network of Arteriopathy (GENOA) was initiated in 1995 to study the genetics of hypertension and its arteriosclerotic complications in sibships. Arteriosclerosis (i.e., atherosclerosis and arteriolosclerosis) of the cardiac, cerebral, renal, and peripheral arteries leads to target organ damage and clinical sequelae such as heart attack, heart failure, stroke, dementia, chronic kidney disease, and claudication. In this application, we propose to conduct an exome-wide association study (Aim 1) and transcriptomic profiling (Aim 2) as cost-effective methods of identifying and studying functional variations in the 1020 GENOA African-American and non-Hispanic White sibships (N=2912) who are at high risk of developing a wide range of arteriosclerotic clinical outcomes. The GENOA cohort provides a unique opportunity to assess the phenotypic impact of rare variants that naturally replicate within a sibship, but may not be seen again even in large epidemiological populations. The GENOA community-based sampling of hypertensive sibships was explicitly designed to study the genetics of multiple late-onset arteriosclerotic diseases that typically become clinically apparent only in the upper generations of families. In order to ultimately identify at risk individuals and estimate the cumulative burden of genetic risk allele in two U.S. populations (Aim 3) we will estimate genetic risk scores and assess the attributable fraction of phenotypic variation explained by these new genetic variations.